Patients with obesity-related phenomena such as insulin resistance, the metabolic syndrome, and Type 2 diabetes mellitus, have a markedly increased risk for atherothrombosis. Investigators now recognize these conditions as representing a major threat to public health and that our current understanding and management strategies of these disorders are inadequate. Studies suggest that excess caloric intake and physical inactivity lead to a neuro-humoral imbalance that promotes obesity and insulin resistance in association with systemic inflammation and dyslipidemia. In the vascular wall, systemic factors and local insulin resistance combine to alter cellular energetics and mitochondrial function, activate innate immunity, and impair the bioavailability of endothelium-derived nitric oxide. We propose to establish a Specialized Center of Clinically-Oriented Research (SCCOR) at Boston University School of Medicine that will take a multi-disciplinary approach to define mechanisms of vascular injury in this setting. We will test the overall hypothesis that obesity and insulin resistance induce inflammation and ectopic lipid deposition in vasculature that impairs vascular function and promotes atherothrombosis. Project 1 (Dr. Vita) will test the hypothesis that inter-related effects of reduced activity of AMP-dependent protein kinase, increased production of mitochondrial-derived reactive oxygen species, and activation of innate immunity contribute to vascular dysfunction in human subjects with early insulin resistance. Project 2 (Dr. Ramachandran) will test the hypothesis that circulating adipokines and neuroendocrine and gut-derived hormones impair vascular function and will prospectively predict risk for developing obesity, hypertension, dyslipidemia, and the metabolic syndrome in the Framingham Heart Study. Project 3 (Dr. Gokce) will test the hypothesis that adipose tissue serves as a primary source of inflammatory cytokines that impair vascular function in obese patients and will examine the impact of specific weight loss strategies on vascular function and inflammation in adipose tissue. Project 4 (Dr. Freedman) will test the hypothesis that innate immunity contributes to atherothrombosis and the acute response to vascular injury by examining toll-like receptor (TLR)-mediated signaling mechanisms in leukocytes and platelets from human subjects and mouse models of obesity. Project 5 (Dr. Hamilton) will use novel magnetic resonance imaging and spectroscopy techniques to test the hypothesis that ectopic lipid deposition is a marker of vascular dysfunction and accelerated atherosclerosis in obesity and the metabolic syndrome. This project takes advantage of the unique expertise of the investigators and research resources at the Boston University Medical Campus, including strong statistical support, outstanding programs of research in basic vascular biology, novel imaging resources, clinical programs for the management of obesity, and the Framingham Heart Study. This work will improve our understanding of vascular injury in insulin resistance and obesity and may identify new approaches for patient management.